Factors Affecting Recurrence of Idiopathic Granulomatous Mastitis: A Systematic Review

Idiopathic granulomatous mastitis is a rare and benign disease that primarily affects young women of reproductive age. Various factors have been suggested as possible causes, including pregnancy, breastfeeding, history of taking birth control pills, hyperprolactinemia, smoking, and history of trauma. Due to unknown etiology, opinions on its treatment have varied, resulting in differing recurrence rates and side effects. Therefore, conducting a comprehensive systematic review and meta-analysis can aid in understanding the causes and recurrence of the disease, thereby assisting in the selection of effective treatment and improving the quality of life. A systematic literature review was conducted using predefined search terms to identify eligible studies related to risk factors and recurrence up to June 2022 from electronic databases. Data were extracted and subjected to meta-analysis when applicable. A total of 71 studies with 4735 patients were included. The mean age of the patients was 34.98 years, and the average mass size was 4.64 cm. About 3749 of these patients (79.17%) were Caucasian. Patients who mentioned a history of pregnancy were 92.65% with 76.57%, 22.7%, and 19.7% having a history of breastfeeding, taking contraceptive pills, and high prolactin levels, respectively. Around 5.6% of patients had previous trauma. The overall recurrence rate was 17.18%, with recurrence rates for treatments as follows: surgery (22.5%), immunosuppressive treatment (14.7%), combined treatment (14.9%), antibiotic treatment (6.74%), and observation (9.4%). Only antibiotic and expectant treatments had significant differences in recurrence rates compared to other treatments (p value = 0.023). In conclusion, factors such as Caucasian race, pregnancy and breastfeeding history, and use of contraceptive hormone are commonly associated with the disease recurrence. Treatment should be tailored based on symptom severity and patient preference, with surgery or immunosuppressive options for recurrence.


Introduction
Idiopathic granulomatous mastitis (IGM) is a rare and benign infammatory mammary disease with an unknown etiology [1].Also known as granulomatous lobulitis or lobular granulomatous mastitis [2], it can be misdiagnosed as furuncle or cellulitis [3].IGM primarily afects premenopausal women, typically between the ages 32 and 36 [4].Various studies have identifed factors that may contribute to the development of IGM, such as age, recent pregnancy [5,6], duration of breastfeeding, history of contraceptive pills usage [6][7][8][9], smoking, and trauma [9,10].Hyperprolactinemia and diabetes have also been linked to the disease [5].It is thought that milk stasis after pregnancy and lactation, combined with hyperprolactinemia, can lead to hypertrophic breast tissue and the development of IGM [1].While IGM has been reported in all races [8], it appears to be more prevalent in certain regions, including the Mediterranean and Asian regions [9].Te disease's clinical manifestation is similar to a breast lump with infammatory symptoms and abscess [11,12] and is typically located in the breast's upper outer quadrant.Occasionally, it can be found in other quadrants, and in some cases, bilaterally [11].Te likelihood of both breasts being afected simultaneously is minimal [9], but the left breast is more commonly involved [2].Unfortunately, this disease has no cure [3,12]; however, in minor cases, it may resolve on its own without any treatment.For severe cases, medical or surgical intervention may be required [13].
Decisions regarding the management of this condition are dependent on the severity of the disease as well as the patient's preferences.Surgery still plays an integral role in its disease [3].Despite receiving appropriate treatments, these masses may persist, recur, or sometimes lead to the development of fstulas, necessitating follow-up in afected patients [14,15].Moreover, the presence of erythema nodosum can further complicate the disease, making its treatment challenging [12].
In general, despite numerous studies in this feld, a specifc reference for the possible causes of this disease has not yet been defned.Although several risk factors have been proposed, there is no comprehensive summary that reviews the available evidence or a systematic review of studies.In addition, there is no consensus on a treatment method.Terefore, we conducted this comprehensive systematic review and meta-analysis to evaluate the risk factors for IGM and assess the likelihood of recurrence.

Methods
We conducted this review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies relevant to underlying factors and recurrence in patients with granulomatous mastitis.
Two investigators performed a comprehensive electronic database search, including PubMed, Cochrane, Embase, and Google Scholar databases.Te search period covered up to June 2022, and there was no time limit in the study selection.Our searches were conducted individually or in diferent combination using the following terms: "mastitis," "granulomatous lobular mastitis," "idiopathic granulomatous mastitis," "recurrence," "risk factors," or etiology.We identifed some additional studies from other sources and excluded studies with insufcient information.Only studies published in English were considered for this review.Te selection process for the studies is summarized in Figure 1.
Tis study included published studies that satisfed the given criteria.Studies related to idiopathic granulomatous mastitis that were conducted with clinical trial methods, descriptive, cohort with or without control, and case control were included in this study.However, studies that described granulomatous mastitis in male or transgender patients were excluded.In addition, letters to the editor, review articles, and clinical reports with less than 4 patients were not included.Furthermore, studies that focused on other types of mastitis, articles that solely discussed radiological manifestations, articles without clinical or therapeutic explanations, and articles in languages other than English were also excluded.Te following data were extracted for each study: name of the frst author, country of origin of the study, year of publication, and the number of patients.Te outcome measures that were extracted were the age of presentation, any association with autoimmune diseases, smoking habits, history of trauma, parity, lactating history, BMI, prolactin levels, clinical symptoms (i.e., presence of a mass, pain, or other symptoms), recurrence, and treatment (antibiotics, corticosteroids, or surgery).
In situations where quantitative data were appropriate for meta-analysis, the averages and ranges were calculated considering the analytic weight.Te analytic weight is determined by the inverse proportionality to the variance of each observation.Typically, the observations represent averages, and the weights correspond to the number of elements contributing to each average.All statistical analyses were performed using SPSS 25 software.Finally, we interpreted the obtained results within the framework of the study's overarching criteria.

Results
Out of the 71 studies reviewed, a total of 4735 patients were included in this study (Table 1).Of these, 69 articles (4566 patients) reported the average age of patients at the time of symptom onset.Te average age across these articles was 34.98 years.Te incidence of the disease across diferent age ranges was not investigated.Racial distribution was reported in all 4735 patients, with 3749 (79.17%) being Caucasian, 543 (11.46%)Asian, and 350 (7.39%) Hispanic.Tere were also 38 Indian, 20 Moroccan, 14 African American, and 21 Jewish patients.Of the 55 publications that examined pregnancy history, 3251 out of 3554 reported on this aspect, accounting for 91.47% of the patients.
Out of the 71 articles, 44 of them mentioned the history of breastfeeding, while only 27 of them did not mention.Among the 3252 patients that were examined in those 44 articles, 2721 of them had a positive history of breastfeeding, indicating an 83.67%rate of breastfeeding.In addition, about 41 articles discussed the history of taking birth control pills, with a total of 3203 patients being examined.Of those patients, 730 had a history of taking contraceptive pills, accounting for 22.79% of patients.Te smoking history of patients was examined in 38 studies, covering 2687 patients.Among these patients, 373 had a history of smoking, which is 13.88% of patients.Furthermore, 16 articles mentioned the history of trauma, manipulation, or surgery in the breasts, including a total of 628 patients.Among these patients, 36 had a positive history of the same, amounting to 5.7%.Prolactin tests were performed in 16 studies with a total of 502 patients being subjected to testing.Among them, 99 patients had high prolactin levels, accounting for 19.7% of patients (19.7%) (Table 2).
Out of the 71 included articles, 37 articles reported the granulomatous mastitis mass sizes for a total of 2151 patients.Te average mass size for these patients was calculated to be 4.64 cm.In 10 studies, the body mass index (BMI) of the patients was discussed, with 4 studies reporting on the average BMI of 198 patients which was found to be 28.24 2).Te variables were also studied based on the Caucasian race and other races, and there was no signifcant relationship with relapse (p � 0.171) (Table 3).Te prevalence of diferent symptoms in patients (mass, pain, infammatory symptoms, lymphadenopathy, skin symptoms, and systemic and infectious symptoms) in the Caucasian race and other races was compared.Except for which is signifcantly higher in other races than the Caucasian race (p value � 0.003), the prevalence of symptoms other than lymphadenopathy in the Caucasian race was not signifcantly diferent from other races (p > 0.05).However, lymphadenopathy was found to be signifcantly higher in other races than in the Caucasian race (p � 0.003).
To categorize the various treatments available for granulomatous mastitis, they were divided into fve distinct groups.Te frst group consisted of surgical procedures, such as drainage, excision, lumpectomy, and others.Te second group of treatment was immunosuppressive drug treatment including prednisolone, methotrexate, and so on.Te third group included combined surgical and immunosuppressive treatments.Te fourth group was dedicated to observation, while it focuses solely on antibiotic treatment.Many patients initially received antibiotic treatment before biopsy or any other treatment.Patients who did not undergo any other therapy, such as surgery or immunosuppressive drug therapy, were placed in the antibiotic group.
Te overall recurrence rate among patients was found to be 17.18%.Among diferent treatment options, the recurrence rate of surgical treatment alone was 22.5%, the recurrence rate for immunosuppressive treatment was 14.7%, the recurrence rate for combined treatment was 14.9%, the recurrence rate for observation was 9.4%, and the recurrence rate for antibiotic treatment alone was calculated to be 6.74%.Table 4 provides a detailed breakdown of these results.Only the recurrence rates for antibiotic and expectant treatment showed signifcant diferences when compared to other treatments (p � 0.023).In addition, when comparing the recurrence rates of all treatments with those for surgical treatment alone, it was found that the recurrence rate for antibiotic and expectant treatments exhibited a signifcant diference compared to the recurrence rate for surgical treatment.Table 4 provides further details on these comparisons.

Discussion
Tis study reviewed 71 articles and 4735 patients with granulomatous mastitis, a chronic infammatory breast disease of unknown etiology.Te incidence of this disease has increased in recent years (9 studies before 2010 compared to 62 studies after 2011), presenting a diagnostic and treatment challenge for clinicians.Our results supported that the disease is four times more prevalent in the Caucasian race, especially in the Mediterranean and Middle East regions, and commonly afects women in their reproductive age.Pregnancy (91.4%) and breastfeeding (83.6%) were the main underlying factors for the disease, followed by use of oral contraceptive pills (OCP) and high prolactin levels.Smoking, trauma, and weight gain had minimal association with the disease.
After considering the epidemiological and racial differences, a reanalysis was conducted on the underlying causes, symptoms, and recurrence rates between the Caucasian race and other races for IGM.Te study found that there was no signifcant diference between the main causes, namely, pregnancy, breastfeeding, and hormone intake in two groups.Terefore, additional cohort and prospective studies are required to investigate other genetic or environmental factors such as nutrition and lifestyle, which might explain why the prevalence of IGM is four times higher in the Caucasian race.In terms of disease   Ref: reference, Rec: recurrence, f/u: follow-up.Newcastle-Ottawa, JBI risk of bias, and Jadad checklists were used for the quality assessment of cohort/case-control, case series, and randomized controlled trial (RCT) studies.

Te Breast Journal
Te Breast Journal manifestation, mass disease purifcation was the most common symptom, followed by pain, infammatory symptoms, lymphadenopathy, and skin involvement, respectively.A comparative analysis between Caucasian and other races exhibited similar clinical symptoms between the two groups, except for lymphadenopathy, which was more frequently observed in the non-Caucasians (p = 0.003).However, since only two studies mentioned this in the group of other races (43 patients out of 108 patients), and with the sample size being small, this outcome needs to be interpreted with caution.Regarding recurrence, an average of 17% of patients experienced it, in all the studies, indicating that current treatments are not associated with complete disease eradication and there could be a recurrence.Even though the recurrence rate is higher in the Caucasian group, it is not statistically signifcant, and it seems that the race or  Various treatments have been mentioned for this disease, ranging from observation to systemic immunosuppressive treatment and surgery.Tus, we classifed the treatments into several categories, including surgical treatment, immunosuppressive treatment, combined treatment, antibiotic treatment, and expectant treatment.As most patients received a course of empiric antibiotics before biopsy and diagnosis, we have classifed studies in the antibiotic category, which only continued antibiotic treatment and did not receive any other systemic treatments or surgery.
Our results showed that surgery alone, immunosuppressive treatment alone, and combined treatment (surgical + immunosuppressive) did not have a statistically signifcant diference in recurrence rates.However, surgery without immunosuppressive treatment had a slightly higher recurrence rate, although the diference was not signifcant.Combined treatment may have treatment-related complications but did not statistically signifcantly reduce the recurrence rate.In line with our results, Li (review of 15 articles) [81] and Xiaojia (review of 21 articles) [82] mentioned that surgery was the best treatment for faster complete remission and adding steroid treatment did not make a diference in complete remission.Tey also reported that the rate of surgical recurrence was small and recommended medical treatment for patients concerned about scarring or future breastfeeding.
Furthermore, in our review, antibiotic treatment alone (without immunosuppression and surgery) and expectant treatment had a lower recurrence rate.However, the number of articles compared to other treatments in each category was small; 5 studies with 53 observed patients and 12 studies with 178 patients treated with antibiotics.Lei et al. [82] recommended systemic steroid treatment in the case of symptoms involving the whole breast, such as infammation, skin involvement, and multiple fstulas.Tey also suggested this treatment in patients with limited symptoms at the beginning of treatment [81,82].Terefore, treatment should be chosen based on the patient's preference, severity of symptoms, and the physician's opinion while considering side efects related to each category such as scarring, deformity, and immunosuppressant drug treatment's side efects and longer treatment duration.
In conclusion, our review of IGM disease has identifed that factors such as Caucasian race, pregnancy and breastfeeding history, and use of contraceptive hormone are commonly associated with the disease.Symptoms and manifestations do not appear to vary signifcantly across diferent races.Incidence rates appear to be increasing as more studies are carried out.With regard to treatment and recurrence, we suggest that a treatment regimen such as surgery or immunosuppressive treatment should be selected based on the severity of symptoms and patient's preference, taking into consideration the complications of each treatment line.Antibiotic and expectant treatments may be used initially and for minor symptoms.

Figure 1 :
Figure 1: Flowchart of the study selection process for this review.
Records identified through date base searching PubMed, ISI web of science, Embase, Cochrane and Scopus datea base ISI web of knowledge after delete of duplications

Table 1 :
Characteristics of studies included and outcome measure.

Table 2 :
Study characteristics: insights from parameter studies.

Table 3 :
Comparison of diferent variables based on the race.

Table 4 :
Comparison of recurrence rates based on diferent treatments.